Uses
CUDC-907 is a dual PI3K and HDAC inhibitor. Studies have shown CUDC-907 is able to enhance antitumor activity when combined with standard of care agents in multiple myeloma and B cell lymphoma xenogra
ft models.
Biological Activity
cudc-907 is a dual-acting inhibitor of hdac and pi3k with ic50 values of 1.7/5.0/1.8/2.8 nm (hdac1/2/3/10) and 19/54/39 nm (pi3k).[1]the phosphoinositide 3-kinases (pi3ks) contain three classes of pi3k each with its own distinct lipid products and specific substrate. they are a family of lipid kinases that regulates a wide range of pathway by propagating intracellular signaling cascades. pi3k phosphorylates the 3’-oh group of phosphatidylinositols. this activated akt, the protein ser/thr-kinase, by recruiting them to the cell membrane. the pi3k/akt signaling pathway is critical in cancer, because it promotes cell growth and survival. the studies have proved that pi3k pathway plays an important role in cancer progression and treatment for lung cancers, breast cancer.[2, 3] histone deacetylases (hdacs) and histone acetyltransferases (hats) mediates the balance between histone deacetylation and acetylation. hdacs also regulate the acetylation status of signaling molecules, chaperones, and transcription factors that are non-histone proteins.[4]cudc-907 is a potent inhibitor of class i pi3k kinases and hdac classes i and ii enzymes. cudc-907 resulted in increase of acetylated histones and non-histone proteins such as tubulin and p53. cudc-907 also induced p21 protein in h460 cell lines. cudc-907 dose-dependently decreases phosphorylation of akt and its downstream targets, p70s6 and 4ebp-1 by inhibiting the pi3k pathway,, in h460 cells. cudc-907 were able to inhibit the activation of mek in cancer cell lines including nsclc h460 cells, breast cancer bt-474 cells and nsclc h1975 cells. cudc-907 suppresses the raf- mek-mapk signaling pathway through hdac inhibition. cudc-907 can also cause the decrease of both p-src) and p-src in rpmi-8226 multiple myeloma cells. cudc-907 induced cell-cycle arrest at g2–m phase at the dose of 1 μm for 24h.[1]cudc-907 inhibited growth of the tumor in daudi cancer cell xenografts dose-dependently. in a xenograft tumor model of dlbcl (su-dhl4 diffuselarge b-cell lymphoma) cudc-907 induced tumor regression after oral administration (100 mg/kg) or intravenous (50 mg/kg). cudc-907 also caused tumor stasis in nsclc cell xenografts [1].
Enzyme inhibitor
This orally available, dual-PI3K/HDAC inhibitor (FW = 508.55 g/mol;
CAS 1339928-25-4); Solubility: 100 mg/mL DMSO; <1 mg/mL Water),
known as N-hydroxy-2- ( ( (2- (6-methoxypyridin-3-yl) -4-morpholino-
thieno[3,2-d]pyrimidin-6-yl) methyl) (methyl) amino) -pyrimidine-5-carbox-
amide, targets the phosphatidylinositol 3-kinase PI3Kɑ, and histone
deacetylases HDAC1, HDAC2, HDAC3 and HDAC10 with IC50 values of
19 nM, 1.7 nM, 5 nM, 1.8 nM and 2.8 nM, respectively. PI3K/HDAC
Inhibitor I inhibits other PI3K isoforms such as PI3Kβ, PI3Kγ, PI3Kδ,
PI3KɑH1047R and PI3KɑE545K with IC50 of 54 nM, 311 nM, 39 nM, 73
nM and 62 nM, respectively. [1] Bao, Wang, Qu, et al., American
Association for Cancer Research Meeting, Chicago, Illinois, Poster # 3744.
in vivo
Oral administration of Fimepinostat inhibits growth of the Daudi cancer cell xenografts in a dose-dependent manner. Tumor stasis is observed at 100 mg/kg in this model without obvious toxicity. Importantly, in the same model, Fimepinostat achieves better efficacy than GDC-0941, SAHA, or a combination of these 2 compounds given at their maximal tolerated doses (MTD). Furthermore, Fimepinostat causes tumor regression or stasis after intravenous (50 mg/kg) or oral administration (100 mg/kg) in a xenograft tumor model of SU-DHL4 diffuse large B-cell lymphoma (DLBCL) and causes tumor stasis in KRAS-mutant A549 NSCLC cell xenografts[1].
IC 50
PI3Kα: 19 nM (IC50); PI3Kδ: 39 nM (IC50); PI3Kβ: 54 nM (IC50); PI3Kγ: 311 nM (IC50); HDAC1: 1.7 nM (IC50); HDAC3: 1.8 nM (IC50); HDAC10: 2.8 nM (IC50); HDAC2: 5 nM (IC50); HDAC11: 5.4 nM (IC50); HDAC6: 27 nM (IC50); HDAC8: 191 nM (IC50); HDAC4: 409 nM (IC50); HDAC7: 426 nM (IC50); HDAC9: 554 nM (IC50); HDAC5: 674 nM (IC50)
References
[1]. qian c, lai cj, bao r, wang dg, wang j, xu gx, atoyan r, qu h, yin l, samson m et al: cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. clin cancer res 2012, 18(15):4104-4113.
[2]. wong kk, engelman ja, cantley lc: targeting the pi3k signaling pathway in cancer. curr opin genet dev 2010, 20(1):87-90.
[3]. engelman ja: targeting pi3k signalling in cancer: opportunities, challenges and limitations. nat rev cancer 2009, 9(8):550-562.
[4]. kim hj, bae sc: histone deacetylase inhibitors: molecular mechanisms of action and
